Deposition of excess collagen and other matrix components in the perisinusoidal (Disse) space is an early response of the liver to administered toxins, such as ethanol and correlates with clincal evidence of hepatic dysfunction. The pathogenesis of this process, at the cellular level, is obscure. The aims of the present project are identification of the cell populations within the liver responsible for deposition of perisinusoidal collagen, characterization of the specific types of collagen represented in the abnormal matrix, examination of possible causative factors (toxins, their metabolites or leukoycte factors) and documentation of collagenolytic activity, which may be responsible in part for turnover of perisinusoidal collagen. The experimental model will be rats or cell cultures exposed to ethanol or carbon tetrachloride. The cell studies will involve recently developed techniques for the individual isolation and primary culture of parenchymal, sinusoidal endothelial and Kupffer cells, respectively, from rat liver. Cells from treated or control animals in homogenous culture will be assayed for collagen synthesis. Co-culture of these isolates also will be carried out in studies of the role of cell-cell interaction on the rate, types and polarity of collagen secretion. This application of culture methodology constitutes a new direct approach to the pathogenesis of hepatic fibrosis. With identification of the cell types contributing to the fibrogenic response, it will be possible to assess at the cellular level the effects of putative initiators of fibrogenesis. Precise characterization of the collagenous components of the matrix elicited by hepatotoxins will provide data essential to an understanding of the way in which altered matrix affects hepatocellular function. Finally, the long-term goal is a rational basis for prophylaxis or therapy of fibrosis, not only in toxin-related disease but potentially also in those hepatic diseases of varying etiology exhibiting a similar pattern of pathological fibrosis.